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Susanne Ledig, Peter Wieacker
The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [MIM 277000] is characterised by the absence of a uterus and vagina in otherwise phenotypically normal women with karyotype 46,XX. Clinically, the MRKH can be subdivided into two subtypes: an isolated or type I form can be delineated from a type II form, which is characterised by extragenital malformations. The so-called Müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia (MURCS) association can be seen as the most severe phenotypic outcome...
2018: Medizinische Genetik: Mitteilungsblatt des Berufsverbandes Medizinische Genetik E.V
Mathilde Lefebvre, Anne Dieux-Coeslier, Geneviève Baujat, Elise Schaefer, Saint-Onge Judith, Anne Bazin, Lucile Pinson, Tania Attie-Bitach, Clarisse Baumann, Melanie Fradin, Genevieve Pierquin, Sophie Julia, Chloé Quélin, Bérénice Doray, Sylvie Berg, Catherine Vincent-Delorme, Laetitia Lambert, Nadine Bachmann, Didier Lacombe, Bertrand Isidor, Nicole Laurent, Roume Joelle, Patricia Blanchet, Sylvie Odent, Dominique Kervran, Nathalie Leporrier, Carine Abel, Karine Segers, Fabienne Guiliano, Emmanuelle Ginglinger-Fabre, Angelo Selicorni, Alice Goldenberg, Salima El Chehadeh, Christine Francannet, Benedicte Demeer, Yannis Duffourd, Christel Thauvin-Robinet, Alain Verloes, Valerie Cormier-Daire, Jean Baptiste Riviere, Laurence Faivre, Julien Thevenon
BACKGROUND: Segmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV...
February 19, 2018: Journal of Medical Genetics
Qiankun Zhu, Nan Wu, Gang Liu, Yangzhong Zhou, Sen Liu, Jun Chen, Jiaqi Liu, Yuzhi Zuo, Zhenlei Liu, Weisheng Chen, Yixin Chen, Jia Chen, Mao Lin, Yanxue Zhao, Yang Yang, Shensgru Wang, Xu Yang, Yufen Ma, Jian Wang, Xiaoli Chen, Jianguo Zhang, Jianxiong Shen, Zhihong Wu, Guixing Qiu
Congenital scoliosis (CS) is a three-dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age- and gender-matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS)...
September 25, 2017: Journal of Cellular and Molecular Medicine
Frederic Koch, Manuela Scholze, Lars Wittler, Dennis Schifferl, Smita Sudheer, Phillip Grote, Bernd Timmermann, Karol Macura, Bernhard G Herrmann
The spinal cord and mesodermal tissues of the trunk such as the vertebral column and skeletal musculature derive from neuro-mesodermal progenitors (NMPs). Sox2, Brachyury (T), and Tbx6 have been correlated with NMP potency and lineage choice; however, their exact role and interaction in these processes have not yet been revealed. Here we present a global analysis of NMPs and their descending lineages performed on purified cells from embryonic day 8.5 wild-type and mutant embryos. We show that T, cooperatively with WNT signaling, controls the progenitor state and the switch toward the mesodermal fate...
September 11, 2017: Developmental Cell
Keiko Watanabe, Yusuke Kobayashi, Kouji Banno, Yusuke Matoba, Haruko Kunitomi, Kanako Nakamura, Masataka Adachi, Kiyoko Umene, Iori Kisu, Eiichiro Tominaga, Daisuke Aoki
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a disease caused by congenital absence of the uterus and two-thirds of the upper vagina. The pathogenic mechanism of MRKHS may involve gene abnormalities, and there are various case reports associating MRKHS with the Wnt family member 4 (Wnt4) mutation. Analysis of genes mapped to regions in which deletion and duplication are frequently detected in patients with MRKHS has shown involvement of LIM homeobox 1 (LHX1), HNF1 homeobox B (HNF1B) and T-box 6 (TBX6)...
August 2017: Biomedical Reports
Zachary T Morrow, Adrienne M Maxwell, Kazuyuki Hoshijima, Jared C Talbot, David J Grunwald, Sharon L Amacher
BACKGROUND: T-box genes encode a large transcription factor family implicated in many aspects of development. We are focusing on two related zebrafish T-box genes, tbx6l and tbx16, that are expressed in highly overlapping patterns in embryonic paraxial mesoderm. tbx16 mutants are deficient in trunk, but not tail, somites; we explored whether presence of tail somites in tbx16 mutants was due to compensatory function provided by the tbx6l gene. RESULTS: We generated two zebrafish tbx6l mutant alleles...
October 2017: Developmental Dynamics: An Official Publication of the American Association of Anatomists
Yukuto Yasuhiko, Yoko Hirabayashi, Ryuichi Ono
Retrotransposons are abundant in mammalian genomes and can modulate the gene expression of surrounding genes by disrupting endogenous binding sites for transcription factors (TFs) or providing novel TFs binding sites within retrotransposon sequences. Here, we show that a (C/T)CACACCT sequence motif in ORR1A, ORR1B, ORR1C, and ORR1D, Long Terminal Repeats (LTRs) of MaLR endogenous retrovirus (ERV), is the direct target of Tbx6, an evolutionary conserved family of T-box TFs. Moreover, by comparing gene expression between control mice (Tbx6 +/-) and Tbx6-deficient mice (Tbx6 -/-), we demonstrate that at least four genes, Twist2, Pitx2, Oscp1, and Nfxl1, are down-regulated with Tbx6 deficiency...
2017: Frontiers in Chemistry
Daniel Concepcion, Andrew J Washkowitz, Akiko DeSantis, Phillip Ogea, Jason I Yang, Nataki C Douglas, Virginia E Papaioannou
Tbx6 is a T-box transcription factor with multiple roles in embryonic development as evidenced by dramatic effects on mesoderm cell fate determination, left/right axis determination, and somite segmentation in mutant mice. The expression of Tbx6 is restricted to the primitive streak and presomitic mesoderm, but some of the phenotypic features of mutants are not easily explained by this expression pattern. We have used genetically-inducible fate mapping to trace the fate of Tbx6-expressing cells in wild-type and mutant embryos to explain some of the puzzling features of the mutant phenotype...
July 15, 2017: Biology Open
Amanda Janesick, Weiyi Tang, Tuyen T L Nguyen, Bruce Blumberg
During vertebrate somitogenesis, retinoic acid is known to establish the position of the determination wavefront, controlling where new somites are permitted to form along the anteroposterior body axis. Less is understood about how RAR regulates somite patterning, rostral-caudal boundary setting, specialization of myotome subdivisions or the specific RAR subtype that is required for somite patterning. Characterizing the function of RARβ has been challenging due to the absence of embryonic phenotypes in murine loss-of-function studies...
June 1, 2017: Development
C J Sheeba, M P O Logan
Members of the T-box gene family have diverse roles during embryogenesis and many play critical roles in the developing limb. This is exemplified by the fact that, in humans, mutations in T-box genes are associated with several congenital syndromes that include limb defects as part of their characteristic spectrum of abnormalities. T-box genes encode for evolutionary conserved transcription factors that include both transcriptional activators and repressors. The hallmark of T-box gene members is the presence of the eponymous DNA-binding T-box domain...
2017: Current Topics in Developmental Biology
G O Pflugfelder, F Eichinger, J Shen
T-box genes are essential for limb development in vertebrates and arthropods. The Drosophila genome encodes eight T-box genes, six of which are expressed in limb ontogenesis. The Tbx20-related gene pair midline and H15 is essential for dorso-ventral patterning of the Drosophila legs. The three Tbx6-related Dorsocross genes are required for epithelial remodeling during wing development. The Drosophila gene optomotor-blind (omb) is the only member of the Tbx2 subfamily in the fly and is predominantly involved in wing development...
2017: Current Topics in Developmental Biology
Kazuki Takeda, Ikuyo Kou, Noriaki Kawakami, Aritoshi Iida, Masahiro Nakajima, Yoji Ogura, Eri Imagawa, Noriko Miyake, Naomichi Matsumoto, Yukuto Yasuhiko, Hideki Sudo, Toshiaki Kotani, Masaya Nakamura, Morio Matsumoto, Kota Watanabe, Shiro Ikegawa
Congenital scoliosis (CS) occurs as a result of vertebral malformations and has an incidence of 0.5-1/1,000 births. Recently, TBX6 on chromosome 16p11.2 was reported as a disease gene for CS; about 10% of Chinese CS patients were compound heterozygotes for rare null mutations and a common haplotype defined by three SNPs in TBX6. All patients had hemivertebrae. We recruited 94 Japanese CS patients, investigated the TBX6 locus for both mutations and the risk haplotype, examined transcriptional activities of mutant TBX6 in vitro, and evaluated clinical and radiographic features...
March 2017: Human Mutation
M Lefebvre, Y Duffourd, T Jouan, C Poe, N Jean-Marçais, A Verloes, J St-Onge, J-B Riviere, F Petit, G Pierquin, B Demeer, P Callier, C Thauvin-Robinet, L Faivre, J Thevenon
Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6...
June 2017: Clinical Genetics
Erin M Hagen, Robert J Sicko, Denise M Kay, Shannon L Rigler, Aggeliki Dimopoulos, Shabbir Ahmad, Margaret H Doleman, Ruzong Fan, Paul A Romitti, Marilyn L Browne, Michele Caggana, Lawrence C Brody, Gary M Shaw, Laura L Jelliffe-Pawlowski, James L Mills
Classic heterotaxy consists of congenital heart defects with abnormally positioned thoracic and abdominal organs. We aimed to uncover novel, genomic copy-number variants (CNVs) in classic heterotaxy cases. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 infants (cases) with classic heterotaxy identified from California live births from 1998 to 2009. CNVs were identified using the PennCNV software. We identified 56 rare CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, not previously linked to classic heterotaxy...
December 2016: Human Genetics
Weisheng Chen, Jiaqi Liu, Dongtang Yuan, Yuzhi Zuo, Zhenlei Liu, Sen Liu, Qiankun Zhu, Guixing Qiu, Shishu Huang, Philip F Giampietro, Feng Zhang, Nan Wu, Zhihong Wu
Congenital vertebral malformation is a series of significant health problems affecting a large number of populations. It may present as an isolated condition or as a part of an underlying syndromes occurring with other malformations and/or clinical features. Disruption of the genesis of paraxial mesoderm, somites or axial bones can result in spinal deformity. In the course of somitogenesis, the segmentation clock and the wavefront are the leading factors during the entire process in which TBX6 gene plays an important role...
August 30, 2016: Oncotarget
Hisato Kondoh, Shinji Takada, Tatsuya Takemoto
The transcription factor gene Sox2, centrally involved in neural primordial regulation, is activated by many enhancers. During the early stages of embryonic development, Sox2 is regulated by the enhancers N2 and N1 in the anterior neural plate (ANP) and posterior neural plate (PNP), respectively. This differential use of the enhancers reflects distinct regulatory mechanisms underlying the genesis of ANP and PNP. The ANP develops directly from the epiblast, triggered by nodal signal inhibition, and via the combined action of TFs SOX2, OTX2, POU3F1, and ZIC2, which promotes the the ANP development and inhibits other cell lineages...
June 2016: Development, Growth & Differentiation
Kohei Yamamizu, Alexei A Sharov, Yulan Piao, Misa Amano, Hong Yu, Akira Nishiyama, Dawood B Dudekula, David Schlessinger, Minoru S H Ko
Mouse embryonic stem cells (ESCs) can differentiate into a wide range - and possibly all cell types in vitro, and thus provide an ideal platform to study systematically the action of transcription factors (TFs) in cell differentiation. Previously, we have generated and analyzed 137 TF-inducible mouse ESC lines. As an extension of this "NIA Mouse ESC Bank," we generated and characterized 48 additional mouse ESC lines, in which single TFs in each line could be induced in a doxycycline-controllable manner. Together, with the previous ESC lines, the bank now comprises 185 TF-manipulable ESC lines (>10% of all mouse TFs)...
2016: Scientific Reports
Smita Sudheer, Jinhua Liu, Matthias Marks, Frederic Koch, Anna Anurin, Manuela Scholze, Anna Dorothea Senft, Lars Wittler, Karol Macura, Phillip Grote, Bernhard G Herrmann
Presomitic mesoderm (PSM) cells are the precursors of the somites, which flank both sides of the neural tube and give rise to the musculo-skeletal system shaping the vertebrate body. WNT and FGF signaling control the formation of both the PSM and the somites and show a graded distribution with highest levels in the posterior PSM. We have used reporters for the mesoderm/PSM control genes T, Tbx6, and Msgn1 to investigate the differentiation of mouse ESCs from the naïve state via EpiSCs to PSM cells. Here we show that the activation of WNT signaling by CHIR99021 (CH) in combination with FGF ligand induces embryo-like PSM at high efficiency...
July 2016: Stem Cells
Noortje Ijssennagger, Aafke W F Janssen, Alexandra Milona, José M Ramos Pittol, Danielle A A Hollman, Michal Mokry, Bark Betzel, Frits J Berends, Ignace M Janssen, Saskia W C van Mil, Sander Kersten
BACKGROUND & AIMS: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA alters hepatic expression of many genes. However, no data are available on the effects of OCA in the human liver. Here we generated gene expression profiles in human precision cut liver slices (hPCLS) after treatment with OCA...
May 2016: Journal of Hepatology
D E J Waschk, A-C Tewes, T Römer, J Hucke, K Kapczuk, C Schippert, P Hillemanns, P Wieacker, S Ledig
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a well-known malformation pattern of the Müllerian ducts (MDs) characterized by congenital absence of the uterus and vagina. To date, most cases remain unexplained at molecular level. As female Wnt9b-/- mice show a MRKHS-like phenotype, WNT9B has emerged as a promising candidate gene for this disease. We performed retrospective sequence analyses of WNT9B in 226 female patients with disorders of the MDs, including 109 patients with MRKHS, as well as in 135 controls...
May 2016: Clinical Genetics
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